TumorImmunology Keyquestions HowdotumorcellsevadetheimmunesystemWhatarethemainimmuneresponsestotumorcells Whatarethepotentialanti tumorimmunotherapies 23 TumorImmunology a Propertiesoftumor transformed cells 1 Abnormalitiesingrowthandresponsestoregulationandapoptosis 2 Inductionbycarcinogens viruses spontaneous 3 Roleofoncogenes e g growth promotingoncogenesandoncoproteins 4 Roleoftumor suppressorgenesandgenesthatcontrolDNArepair CORE CancerCanceriscausedbyabnormalandinvasivegrowthoftumorcellsItaccountsfor20 ofdeathinindustrializedcountries 6millionnewcancerpatientseachyearworldwide Generally canceroccurslateinlife Causedbyaccumulatedmutationsinthegenescontrollingcellgrowthanddeath Currenttreatments surgery radiationandcytotoxicdrugsFuturetreatments smallmoleculedrugsthatspecificallyinhibittumorcellgrowth immunotherapy CarcinogensinducemutationsinDNA ChemicalcarcinogensRadiationOncogenicviruses chronicinfection inflammation Accumulationofmutationsleadstocancercells Thegrowthandlifespanofatypicalhumantumor Benignvs malignanttumorsBreasttumorsforexample Malignantcellsaremoreaggressiveingrowth andtheyspreadtonearbytissuesortodifferentorgansthroughlymphandbloodvessels Metastasis Carcinoma epithelialcelltumorsLeukemia tumorsofcirculatingcellsLymphoma solidtumorsinlymphnodesMyeloma tumorsofbonemarrowcellsSarcoma tumorsofconnectivetissuecells Terminologies Virusesareassociatedwithsomehumancancers SomeviralproteinsinduceuncheckedproliferationofhumancellsbytargetinggenessuchasP53andRb Cantumorcellsfromapersongrowinanotherperson Usually no Butsometimes yes Largely itdependsontheMHChaplotypeofdonorsandrecipients Howdoimmunecellsdetecttumorcells CD4 CD8 NKcellsandBcells Theylookfortumorantigens antigensdifferentiallyexpressedbytumorcellsandnormalcells Tumorantigens Changesinthegenomeoftumorcellscanleadtotheexpressionoftumorantigens whicharenot tumor specificantigens orlessexpressedinnormalcells tumor associatedantigens b Tumor specificandtumor associatedantigens 1 Tumor specificsharedantigens melanomaantigen 1 MAGE 1 foundonmelanomasandothertransformedcells 2 Tissue specificantigens onnormalandtransformedcells suchastyrosinasefoundonnormalandtransformedmelanocytes 3 Antigensresultingfrommutation suchasmutationsofoncogenes 4 Overexpressedantigens antigensexpressedatabnormalstageofdevelopmentViralantigensOthercancerindicators a Oncofetalantigens Carcinoembryonicantigen CEA ColoncancerAlpha fetoprotein Liverandtestiscancer b Differentiationantigens Commonacutelymphoblasticleukemiaantigen CALLA alsocalledCD10 foundoncellsofacutelymphoblasticleukemiaPSA Prostatecancer CORE TumorantigensQualitativeand orquantitativechangesinantigen TumorEpitopeEscape MutationofanchorresiduesMutationofTCRcontactresiduesNoCTLrecognitionAntagonisticEpitope negativesignaltoCTL AlteredPeptideLigand APL MutationaffectingantigenprocessingWithinepitopeaffectingstabilityofepitopeOutsideofepitopeefficiencyofepitopeprocessing Tumorantigens ExamplesoftumorantigensrecognizedbyCD8Tcells c Anti tumorimmunity 1 CMI TC TH1cytokines NK macrophage 2 Humoral ADCCandactivationofcomplement 3 Immunosurveillance Thereisanincreasedfrequencyofcancersinimmunocompromisedindividuals however mostcancersoccurinindividualswithnoovertimmunodeficiency Morelikelythattumorsdevelopwaysofevadingtheimmunesystem CORE Anti tumorimmunityCell mediatedimmuneresponse CD4Tcells controlotherimmunecellsbycytokinesCD8Tcells directlysisNKcells directlysisEosinophils degranulationHumoralresponsebyBcells Antibodiestotumorcells1 facilitateNKcell mediatedlysisoftumorcells2 activatecomplementreaction NKcellscanattacktumorcellslackingMHCIexpression NKcells tumorcells TumorantigenspecificCD4 andCD8 Tcells Figure12 52 DCspresenttumorantigenstoCD4andCD8Tcells MembranefusionallowspresentationoftumorAgtoCD8Tcells Howdotumorsevadeimmuneresponses Examplesoftumorevasion out growthofantigen negativevariantslossorreducedexpressionofMHCproteinssecretionofimmunosuppressivecytokines d inducingCTLapoptosis e lackofco stimulatorysignalssolubletumorantigens CORE Mechanismsoftumorcellevasionofanti tumorcellsDefectiveinoneormoreoftheirMHCclassIexpression 30 50 oftumorsaredefectiveinMHCIexpression Productionofsuppressivecytokines TGF betaandTh2cytokines whichsuppresscell mediatedimmuneresponseLackofco stimulatorysignalsOut growthofantigen negativevariantsSheddingofMHCclassI relatedchain MIC aligandofNKG2DthatisanactivatingNKcellreceptor byepithelialtumorcellstoinhibitNKG2D NKcells Figure12 50 LossofMHCclassIexpressioninprostatetumorcells d Immunotherapy 1 Non specificstimulation adjuvanttherapy 2 Activeimmunizationwithtumorantigens roleofco stimulatorymolecules 3 Cytokinetherapy 4 Adoptivecellularimmunotherapy LAKcells TIL 5 Anti tumorantibodies coupledtocytotoxinsorradioisotopes CORE Non specificadjuvanttherapyIntroductionofBCGvaccine killedmycobacterium intothebladderisatreatmentforsuperficialbladdercancerThismaybebecause BacterialproductsoradjuvantsincreasetheTcellresponsebyactivatingantigenpresentingcellsandothercellsthroughTLRs Thiswillalsoinduceco stimulationmoleculesandMHCmoleculesonAPCs PotentialimmunotherapiesagainsttumorcellsAntibodyagainsttumorantigen immunotoxinsandinductionofADCCbyNKcells Tumorvaccines tumorstakenatsurgeryaremanipulatedexvivo outofbody andareusedasvaccine ThismanipulationincludesexpressingB7 GM CSForIL 12intumorcells Tumorantigenscanbeusedasvaccinestoo e g CEA carcinoembryonicantigen HSP heatshockprotein andtelomerase Dendriticcelltherapy dendriticcellsareisolatedfrompatientsandareloadedwithtumorantigenpeptidesinvitro Thesecellsareinjectedintopatientstoboostanti tumorTcellresponse Tcelltherapy patients Tcells activatedinvitrowithtumorantigensandcytokines IL 12 areinjectedbacktothepatients MonoclonalantibodiesforcancertherapyRituxan Anti CD20 acellsurfacemarkerfoundonmostBcells Certainnon Hodgkinslymphomas Herceptin Anti EFG receptor 2 alsoknownasHER2 ErbB2orNeu whichisoverexpressedin 25perce